PROJECT SUMMARY/ABSTRACT The discovery that individuals with Trisomy 21, or Down syndrome (DS) have neuropathological features identical to those with sporadic Alzheimer's disease (AD) played a critical role in the identification of the amyloid precursor protein gene on chromosome 21 supporting the amyloid cascade hypothesis. People with DS have a lifetime risk for dementia in excess of 75% and comprise the world's largest population of genetically-determined AD. Just as studying DS helped identify the role of amyloid precursor protein mutations in AD pathogenesis, it is also likely to inform us of the potential benefit of manipulating the amyloid pathway on treatment outcomes in AD. It is critically important to the DS population and to the AD therapeutics field to conduct clinical trials, particularly those targeting amyloid accumulation, in individuals with DS. With this application, we propose to utilize the existing depth and breadth of expertise of the NIA-funded Alzheimer's Clinical Trial Consortium (ACTC) to conduct AD clinical trials in adults with DS across performance sites with expertise in DS including the Alzheimer's Biomarker Consortium for Down Syndrome (ABC-DS). As part of an NIH award received last year, we established the ACTC-DS network which includes working groups comprised of leaders from ACTC, ABC-DS and the European Horizon21 DS network to develop the collaborations, infrastructure and plans required to conduct AD clinical trials in DS. During the proposed R61 `Trial Readiness Phase' of the present project, in Aim 1, we will enroll 120 adults with DS (ages 35-55) across 15 sites into a trial ready cohort (TRC) to collect outcome measures and biomarkers harmonized with those being collected in the ongoing ABC- DS study (n = ~400). In Aim 2, we will determine the relationships between cognitive measures and AD biomarkers to identify endpoints for clinical trials that best reflect disease progression. During the R33 `Clinical Trial' phase, for Aim 3, we propose to implement a phase II randomized, double-blind, placebo-controlled trial to evaluate the safety and tolerability of a promising anti-amyloid therapeutic among individuals the TRC. In Aim 4, we will determine the impact of this agent on biomarker evidence of disease modification. Fundamentally, this project will serve to bring AD therapies to the DS population by leveraging the infrastructure of ACTC and incorporating the experience and expertise of the ABC-DS and Horizon21 networks. Beyond the proposed trial, this will establish the means and methods to conduct future therapeutic trials in this population. The potential impact of this approach on improving the lives of adults with DS as well as the general population cannot be overstated.